- Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture
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The viral serine protease NS2B-NS3 is one of the promising targets for drug discovery against dengue virus and other flaviviruses. The molecular recognition preferences of the protease favor basic, positively charged moieties as substrates and inhibitors, which leads to pharmacokinetic liabilities and off-target interactions with host proteases such as thrombin. We here present the results of efforts that were aimed specifically at the discovery and development of noncharged, small-molecular inhibitors of the flaviviral proteases. A key factor in the discovery of these compounds was a cellular reporter gene assay for the dengue protease, the DENV2proHeLa system. Extensive structure-activity relationship explorations resulted in novel benzamide derivatives with submicromolar activities in viral replication assays (EC50 0.24 μM), selectivity against off-target proteases, and negligible cytotoxicity. This structural class has increased drug-likeness compared to most of the previously published active-site-directed flaviviral protease inhibitors and includes promising candidates for further preclinical development.
- Kühl, Nikos,Leuthold, Mila M.,Behnam, Mira A. M.,Klein, Christian D.
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supporting information
p. 4567 - 4587
(2021/05/06)
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- NOVEL MATERIAL FOR SKIN WHITENING, COMPOSITION COMPRISING THE SAME AND METHODS FOR MANUFACTURING THE SAME
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In the present specification, disclosed are a novel material for whitening, a composition containing the material, and a method for manufacturing the material. The material for whitening according to an aspect of the present invention has no toxicity to skin cells and has an excellent melanin biosynthesis inhibitory effect, thereby being able to be utilized as the composition for whitening or a composition for preventing or alleviating chloasma.COPYRIGHT KIPO 2020
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Paragraph 0046; 0048; 0049
(2020/05/19)
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- Synthesis, biological evaluation, and docking studies of PAR2-AP-derived pseudopeptides as inhibitors of kallikrein 5 and 6
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A series of protease activated receptor 2 activating peptide (PAR2-AP) derivatives (1-15) were designed and synthesized. The obtained compounds were tested on a panel of human kallikreins (hKLK1, hKLK2, hKLK5, hKLK6, and hKLK7) and were found completely i
- Severino, Beatrice,Fiorino, Ferdinando,Corvino, Angela,Caliendo, Giuseppe,Santagada, Vincenzo,Assis, Diego Magno,Oliveira, Juliana R.,Juliano, Luiz,Manganelli, Serena,Benfenati, Emilio,Frecentese, Francesco,Perissutti, Elisa,Juliano, Maria Aparecida
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- High-throughput synthesis and optimization of thrombin inhibitors via urazole α-addition and Michael addition
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A novel α-addition of propiolates to urazoles followed by Michael addition of a variety of nucleophiles has been developed for rapid production and optimization of peptidomimetic drug leads. This technology has produced a number of highly potent and selective inhibitors of the serine protease, thrombin.
- Boatman, P. Douglas,Urban, Jan,Nguyen, Minh,Qabar, Maher,Kahn, Michael
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p. 1445 - 1449
(2007/10/03)
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- Large-scale syntheses of FMOC-protected non-proteogenic amino acids: Useful building blocks for combinatorial libraries
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Convenient and reliable large-scale procedures for the protection of various amino acids with N-(9-fluorenylmethoxycarbonyl)oxysuccinimide (FMOC-OSu) are described. Commercially available 4-aminomethylbenzoic acid and trans-4-(aminomethyl)cyclohexanecarbo
- Dener, Jeffrey M.,Fantauzzi, Pascal P.,Kshirsagar, Tushar A.,Kelly, Daphne E.,Wolfe, Aaron B.
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p. 445 - 449
(2013/09/07)
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